Conformationally constrained compounds as pharmaceutical agents

ABSTRACT

Novel substituted amino acids of formula                    
     are disclosed and are useful as agents in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. Processes for the preparation and intermediates useful in the preparation are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 09/622,429 filed Aug.16, 2000, now U.S. Pat. No. 6,316,638, which is a 371 filing ofPCT/US99/09134 filed Apr. 28, 1999, priority based on ProvisionalApplication No. 60/086,694 filed May 26, 1998.

BACKGROUND OF THE INVENTION

Compounds of formula

wherein R₁ is hydrogen or a lower alkyl radical and n is 4, 5, or 6 areknown in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No.4,087,544. The uses disclosed are: protective effect against crampinduced by thiosemicarbazide; protective action against cardiazolecramp; the cerebral diseases, epilesy, faintness attacks, hypokinesia,and cranial traumas; and improvement in cerebral functions. Thecompounds are useful in geriatric patients. The patents are herebyincorporated by reference.

SUMMARY OF THE INVENTION

The compounds, prodrugs, and pharmaceutically acceptable salts areuseful in a variety of disorders. The disorders include: epilepsy,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, depression, anxiety, panic, pain, and neuropathologicaldisorders.

The compounds are those of formula

or a pharmaceutically acceptable salt thereof or a prodrug thereofwherein R₁ to R₁₀ are each independently selected from hydrogen or astraight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl;

m is an integer of from 0 to 3;

n is an integer of from 1 to 2;

o is an integer of from 0 to 3;

p is an integer of from 1 to 2;

q is an integer of from 0 to 2;

r is an integer of from 1 to 2;

s is an integer of from 1 to 3;

t is an integer of from 0 to 2; and

u is an integer of from 0 to 1.

Novel intermediates useful in the preparation of the final compoundsare, for example:

2-Benzyl-2-aza-spiro[4.5]decane-4,4-dicarboxylic acid dimethyl esterhydrochloride;

2-Aza-spiro[4.5]decane-4,4-dicarboxylic acid dimethyl esterhydrochloride;

1-Benzyloxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acid tert-butylester;

1-Hydroxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acid tert-butylester;

2-Aza-spiro[3.5]nonane-1,2-dicarboxylic acid 2-tert-butyl ester;

[3aS-(3α7aα)]-7a-tert-Butoxycarbonylmethyl-1-oxo-octahydro-isoindole-2-carboxylicacid tert-butyl ester; and

[3aS-(α7aα)]-3a-tert-Butoxycarbonylmethyl-octahydro-isoindole-2-carboxylicacid tert-butyl ester.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the instant invention and their pharmaceuticallyacceptable salts and prodrugs are as defined by Formula I to VIII above.

Preferred compounds are those of Formula I above.

Especially preferred are those of Formula I wherein

R₁ to R₁₀ is hydrogen;

m is of from 0to 3, and

n is 1 or 2.

More especially preferred are those compounds selected from:

(±)-2-Aza-spiro[3.5]nonane-1-carboxylic acid hydrochloride;

(±)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride;

(R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride;

(S)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride; and

(R)-2-Aza-spiro[4.5]decane4-carboxylic acid.

Other preferred compounds are those of Formula II above.

Especially preferred are those of Formula II wherein

R₁ to R₁₀ is hydrogen,

o is from 0 to 3; and,

p is 1 to 2.

Other preferred compounds are those of Formula III above wherein

R₁ to R₁₀ is hydrogen,

q is from 0 to 2; and

r is 1 to 2.

Especially preferred is(±)-[3aS-(3α7aα)]-(Octahydro-isoindol-3a-yl)-acetic acidtrifluoroacetate.

Also especially preferred are compounds selected from:

7-Methyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;

[4α,5β(R*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[4α,5α(S*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[4α,5α(R*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

[4α,5β(S*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

7,8-Dimethyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;

7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

7,9-Dimethyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

Spiro[bicyclo[3.3.1]nonane-9,3′-pyrrolidine]-4′-carboxylic acid;

Spiro[pyrrolidine-3,2′-tricyclo[3.3.1.1^(3,7)]decane]-4-carboxylic acid;

3-Amino-6-methyl-spiro[3.5]nonane-1-carboxylic acid;

3-Amino-6,8-dimethyl-spiro[3.5]nonane-1-carboxylic acid;

4-Amino-7-methyl-spiro[4.5]decane-1-carboxylic acid;

4-Amino-7,9-dimethyl-spiro[4.5]decane-1-carboxylic acid;

3-Amino-6-methyl-spiro[3.4]octane-1-carboxylic acid;

3-Amino-6,7-dimethyl-spiro[3.4]octane-1-carboxylic acid;

4-Amino-7-methyl-spiro[4.4]nonane-1-carboxylic acid; and

4-Amino-7,8-dimethyl-spiro[4.4]nonane-1-carboxylic acid.

Pharmaceutical compositions comprising a therapeutically effectiveamount of a compound of Formulas I-VIII above are included in theinstant invention.

Methods of using the compounds of the invention as agents for treatingepilepsy, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, depression, anxiety, panic, pain, andneuropathological disorders are part of the invention,

The term “alkyl” is a straight or branched group of from 1 to 6 carbonatoms including but not limited to methyl, ethyl, propyl, n-propyl,isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, and n-hexyl.

Preferred groups are methyl and tert-butyl.

The benzyl and phenyl groups may be unsubstituted or substituted by from1 to 3 substituents selected from halogen, alkyl, alkoxy, hydroxy,carboxy, carboalkoxy, trifluoromethyl, and nitro.

Halogen includes fluorine, bromine, chlorine, and iodine.

Since amino acids are amphoteric, pharmacologically compatible saltswhen R is hydrogen can be salts of appropriate inorganic or organicacids, for example, hydrochloric, sulphuric, phosphoric, acetic, oxalic,lactic, citric, malic, salicylic, malonic, maleic, succinic, andascorbic. Starting from corresponding hydroxides or carbonates, saltswith alkali metals or alkaline earth metals, for example, sodium,potassium, magnesium, or calcium are formed. Salts with quaternaryammonium ions can also be prepared with, for example, thetetramethyl-ammonium ion.

Prodrugs of compounds I-VIII are included in the scope of the instantinvention. Aminoacyl-glycolic and -lactic esters are known as prodrugsof amino acids (Wermuth C. G., Chemistry and Industry, 1980:433-435).The carbonyl group of the amino acids can be esterified by known means.Prodrugs and soft drugs are known in the art (Palomino E., Drugs of theFuture, 1990;15(4):361-368). The last two citations are herebyincorporated by reference.

The effectiveness of an orally administered drug is dependent upon thedrug's efficient transport across the mucosal epithelium and itsstability in enterohepatic circulation. Drugs that are effective afterparenteral administration but less effective orally, or whose plasmahalf-life is considered too short, may be chemically modified into aprodrug form.

A prodrug is a drug which has been chemically modified and may bebiologically inactive at its site of action, but which may be degradedor modified by one or more enzymatic or other in vivo processes to theparent bioactive form.

This chemically modified drug, or prodrug, should have a differentpharmacokinetic profile to the parent, enabling easier absorption acrossthe mucosal epithelium, better salt formulation and/or solubility,improved systemic stability (for an increase in plasma half-life, forexample). These chemical modifications may be

1) ester or amide derivatives which may be cleaved by, for example,esterases or lipases. For ester derivatives, the ester is derived fromthe carboxylic acid moiety of the drug molecule by known means. Foramide derivatives, the amide may be derived from the carboxylic acidmoiety or the amine moiety of the drug molecule by known means.

2) peptides which may be recognized by specific or nonspecificproteinases. A peptide may be coupled to the drug molecule via amidebond formation with the amine or carboxylic acid moiety of the drugmolecule by known means.

3) derivatives that accumulate at a site of action through membraneselection of a prodrug form or modified prodrug form,

4) any combination of 1 to 3.

Current research in animal experiments has shown that the oralabsorption of certain drugs may be increased by the preparation of“soft” quaternary salts. The quaternary salt is termed a “soft”quaternary salt since, unlike normal quaternary salts, e.g., R—N+(CH₃)₃,it can release the active drug on hydrolysis.

“Soft” quaternary salts have useful physical properties compared withthe basic drug or its salts. Water solubility may be increased comparedwith other salts, such as the hydrochloride, but more important theremay be an increased absorption of the drug from the intestine. Increasedabsorption is probably due to the fact that the “soft” quaternary salthas surfactant properties and is capable of forming micelles andunionized ion pairs with bile acids, etc., which are able to penetratethe intestinal epithelium more effectively. The prodrug, afterabsorption, is rapidly hydrolyzed with release of the active parentdrug.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures. thereof. Forexample, the compound of Example 1 is a mixture of all four possiblestereoisomers. The compound of Example 6 is one of the isomers. Theconfiguration of the cyclohexane ring carbon centers may be R or S inthese compounds where a configuration can be defined.

The radioligand binding assay using [³H]gabapentin and the α₂δ subunitderived from porcine brain tissue was used (Gee N. S., Brown J. P.,Dissanayake V. U. K., Offord J., Thurlow R., Woodruff G. N., “The NovelAnti-convulsant Drug, Gabapentin, Binds to the α₂δ Subunit of a CalciumChannel,” J. Biol. Chem., 1996;271:5879-5776).

TABLE 1 IC₅₀ (μM) at α₂δ Binding Compound Structure Site(±)-2-Aza-spiro[4.5]decane-4- carboxylic acid hydrochloride

0.35 (R)-2-Aza-spiro[4.5]decane-4- carboxylic acid hydrochloride

0.16 (S)-2-Aza-spiro[4.5]decane-4- carboxylic acid hydrochloride

>10 (±)-2-Aza-spiro[3.5]nonane-1- carboxylic acid hydrochloride

1.5  (±)-[3aS-(3α,7aα)]- (Octahydro-isoindol-3a-yl)- acetic acidtrifluoroacetate

>10 Spiro[pyrrolidine-3,2′- tricyclo[3.3.1.1^(3,7)]decane]-4- carboxylicacid

0.42 Spiro[bicyclo[3.3.1]nonane- 9,3′-pyrrolidine]-4′-carboxylic acid

0.57

Table 1 above shows the binding affinity of the compounds of theinvention to the α₂δ Subunit.

The compounds of the invention are compared to Neurontin®, a marketeddrug effective in the treatment of such disorders as epilepsy.Neurontin® is 1-(aminomethyl)-cyclohexaneacetic acid of structuralformula

Gabapentin (Neurontin®) is about 0.10 to 0.12 μM in this assay. Thecompounds of the instant invention are expected, therefore, to exhibitpharmacologic properties comparable to gabapentin. For example, asagents for convulsions, anxiety, and pain.

The present invention also relates to therapeutic use of the compoundsof the mimetic as agents for neurodegenerative disorders.

Such neurodegenerative disorders are, for example, Alzheimer's disease,Huntington's disease, Parkinson's disease, and Amyotrophic LateralSclerosis.

The present invention also covers treating neurodegenerative disorderstermed acute brain injury. These include but are not limited to: stroke,head trauma, and asphyxia.

Stroke refers to a cerebral vascular disease and may also be referred toas a cerebral vascular incident (CVA) and includes acute thromboembolicstroke. Stroke includes both ,focal and global ischemia. Also, includedare transient cerebral ischemic attacks and other cerebral vascularproblems accompanied by cerebral ischemia. A patient undergoing carotidendarterectomy specifically or other cerebrovasculatr or vascularsurgical procedures in general, or diagnostic vascular proceduresincluding cerebral angiography and the like.

Other incidents are head trauma, spinal cord trauma, or injury fromgeneral anoxia, hypoxia, hypoglycemia, hypotension as well as similarinjuries seen during procedures from embole, hyperfusion, and hypoxia.

The instant invention would be useful in a range of incidents, forexample, during cardiac bypass surgery, in incidents of intracranialhemorrhage, in perinatal asphyxia, in cardiac arrest, and statusepilepticus.

Pain refers to acute as well as chronic pain.

Acute pain is usually short-lived and is associated with hyperactivityof the sympathetic nervous system. Examples are postoperative pain andallodynia.

Chronic pain is usually defined as pain persisting from 3 to 6 monthsand includes somatogenic pains and psychogenic pains. Other pain isnociceptive.

Still other pain is caused by injury or infection of peripheral sensorynerves. It includes, but is not limited to pain from peripheral nervetrauma, herpes virus infection, diabetes mellitus, causalgia, plexusavulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain isalso caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Neuropathic pain includes, but is not limited to paincaused by nerve injury such as, for example, the pain diabetics sufferfrom.

Psychogenic pain is that which occurs without an organic origin such aslow back pain, atypical facial pain, and chronic headache.

Other types of pain are: inflammatory pain, osteoarthritic pain,trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legsyndrome, acute herpetic and postherpetic neuralgia, causalgia, brachialplexus avulsion, occipital neuralgia, gout, phantom limb, burn, andother forms of neuralgia, neuropathic and idiopathic pain;syndrome.

A skilled physician will be able to determine the appropriate situationin which subjects are susceptible to or at risk of, for example, strokeas well as suffering from stroke for administration by methods of thepresent invention.

The compounds of the invention are also expected to be useful in thetreatment of depression. Depression can be the result of organicdisease, secondary to stress associated with personal loss, oridiopathic in origin. There is a strong tendency for familial occurrenceof some forms of depression suggesting a mechanistic cause for at leastsome forms of depression. The diagnosis of depression is made primarilyby quantification of alterations in patients' mood. These evaluations ofmood are generally performed by a physician or quantified by aneuropsychologist using validated rating scales, such as the HamiltonDepression Rating Scale or the Brief Psychiatric Rating Scale. Numerousother scales have been developed to quantify and measure the degree ofmood alterations in patients with depression, such as insomnia,difficulty with concentration, lack of energy, feelings ofworthlessness, and guilt. The standards for diagnosis of depression aswell as all psychiatric diagnoses are collected in the Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition) referred to asthe DSM-IV-R manual published by the American Psychiatric Association,1994.

GABA is an inhibitory neurotransmitter with the central nervous system.Within the general context of inhibition, it seems likely thatGABA-mimetics might decrease or inhibit cerebral function and mighttherefore slow function and decrease mood leading to depression.

The compounds of the instant invention may produce an anticonvulsanteffect through the increase of newly created GABA at the synapticjunction. If gabapentin does indeed increase GABA levels or theeffectiveness of GABA at the synaptic junction, then it could beclassified as a GABA-mimetic and might decrease or inhibit cerebralfunction and might, therefore, slow function and decrease mood leadingto depression.

The fact that a GABA agonist or GABA-mimetic might work just theopposite way by increasing mood and thus, be an antidepressant, is a newconcept, different from the prevailing opinion of GABA activityheretofore.

The compounds of the instant invention are also expected to be useful inthe treatment of anxiety and of panic as demonstrated by means ofstandard pharmacological procedures.

MATERIAL AND METHODS

Carrageenin-Induced Hyperalgesia

Nociceptive pressure thresholds were measured in the rat paw pressuretest using an analgesimeter (Randall-Selitto method: Randall L. O. andSelitto J. J., “A method for measurement of analgesic activity oninflamed tissue,” Arch. Int. Pharmacodyn., 1957;4:409-419). MaleSprague-Dawley rats (70-90 g) were trained on this apparatus before thetest day. Pressure was gradually applied to the hind paw of each rat andnociceptive thresholds were determined as the pressure (g) required toelicit paw withdrawal. A cutoff point of 250 g was used to prevent anytissue damage to the paw. On the test day, two to three baselinemeasurements were taken before animals were administered 100 μL of 2%carrageenin by intraplantar injection into the right hind paw.Nociceptive thresholds were taken again 3 hours after carrageenin toestablish that animals were exhibiting hyperalgesia. Animals were dosedwith either gabapentin (3-300 mg, s.c.), morphine (3 mg/kg, s.c.) orsaline at 3.5 hours after carrageenin and nociceptive thresholds wereexamined at 4, 4.5, and 5 hours postcarrageenin.

(R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride was tested inthe above carrageenan-induced hyperalgesia model. The compound was dosedorally at 30 mg/kg, and 1 hour postdose gave a percent of maximumpossible effect (MPE) of 53%. At 2 hours postdose, it gave only 4.6% ofMPE.

Semicarbazide-Induced Tonic Seizures

Tonic seizures in mice are induced by subcutaneous administration ofsemicarbazide (750 mg/kg). The latency to the tonic extension offorepaws is noted. Any mice not convulsing within 2 hours aftersemicarbazide are considered protected and given a maximum latency scoreof 120 minutes.

Animals

Male Hooded Lister rats (200-250 g) are obtained from Interfauna(Huntingdon, UK) and male TO mice (20-25 g) are obtained from Bantin andKingman (Hull, UK). Both rodent species are housed in groups of six. TenCommon Marmosets;(Callithrix Jacchus) weighing between 280 and 360 g,bred at Manchester University Medical School (Manchester, UK) are housedin pairs. All animals are housed under a 12-hour light/dark cycle(lights on at 07.00 hour) and with food and water ad libitum.

Drug Administration

Drugs are administered either intraperitoneally (IP) or subcutaneously(SC) 40 minutes before the test in a volume of 1 mL/kg for rats andmarmosets and 10 mL/kg for mice.

Mouse Light/Dark Box

The apparatus is an open-topped box, 45 cm long, 27 cm wide, and 27 cmhigh, divided into a small (2/5) and a large (3/5) area by a partitionthat extended 20 cm above the walls (Costall B., et al., “Exploration ofmice in a black and white box: validation as a model of anxiety,”Pharmacol. Biochem. Behav., 1989;32:777-785).

There is a 7.5×7.5 cm opening in the center of the partition at floorlevel. The small compartment is painted black and the large compartmentwhite. The white compartment is illuminated by a 60-W tungsten bulb. Thelaboratory is illuminated by red light. Each mouse is tested by placingit in the center of the white area and allowing it to explore the novelenvironment for 5 minutes. The time spent in the illuminated side ismeasured (Kilfoil T., et al., “Effects of anxiolytic and anxioenic drugson exploratory activity in a simple model of anxiety in mice,”Neuropharmacol., 1989;28:901-905).

Rat Elevated X-Maze

A standard elevated X-maze (Handley S. L., et al., “Effects ofalpha-adrenoceptor agonists and antagonists in a maze-exploration modelof ‘fear’-motivated behavior,” Naunyn-Schiedeberg's Arch. Pharmacol,1984;327:1-5), was automated as previously described (Field, et al.,“Automation of the rat elevated X-maze test of anxiety,” Br. JPharmacol., 1991; 102(Suppl.):304P). The animals are placed on thecenter of the X-maze facing one of the open arms. For determininganxiolytic effects the entries and time spent on the end half sectionsof the open arms is measured during the 5-minute test period (Costall,et al., “Use of the elevated plus maze to assess anxiolytic potential inthe rat,” Br. J Pharmacol., 1989;96(Suppl.):312p).

Marmoset Human Threat Test

The total number of body postures exhibited by the animal towards thethreat stimulus (a human standing approximately 0.5 m away from themarmoset cage and staring into the eyes of the marmoset) is recordedduring the 2-minute test period. The body postures scored are slitstares, tail postures, scent marking of the cage/perches, piloerection,retreats, and arching of the back. Each animal is exposed to the threatstimulus twice on the test day before and after drug treatment. Thedifference between the two scores is analyzed using one-way analysis ofvariance followed by Dunnett's t-test. All drug treatments are carriedout SC at least 2 hours after the first (control) threat. Thepretreatment time for each compound is 40 minutes.

Rat Conflict Test

Rats are trained to press levers for food reward in operant chambers.The schedule consists of alternations of four 4-minute unpunishedperiods on variable interval of 30 seconds signaled by chamber lights onand three 3-minute punished periods on fixed ratio 5 (by footshockconcomitant to food delivery) signaled by chamber lights off. The degreeof footshock is adjusted for each rat to obtain approximately 80% to 90%suppression of responding in comparison with unpunished responding. Ratsreceive saline vehicle on training days.

DBA2 Mouse Model of Anticonvulsant Efficacy

All procedures were carried out in compliance with the NIH Guide for theCare and Use of Laboratory Animals under a protocol approved by theParke-Davis Animal Use Committee. Male DBA/2 mice, 3 to 4 weeks old wereobtained from Jackson Laboratories, Bar Harbour, Me. Immediately beforeanticonvulsant testing, mice were placed upon a wire mesh, 4 inchessquare, suspended from a steel rod. The square was slowly invertedthrough 180° and mice observed for 310 seconds. Any mouse falling fromthe wire mesh was scored as ataxic (Coughenour L. L., McLean J. R.,Parker R. B., “A new device for the rapid measurement of impaired motorfunction in mice,” Pharm. Biochem. Behav., 1977;6(3):351-3). Mice wereplaced into an enclosed acrylic plastic chamber (21 cm height,approximately 30 cm diameter) with a high-frequency speaker (4 cmdiameter) in the center of the top lid. An audio signal generator(Protek model B-810) was used to produce a continuous sinusoidal tonethat was swept linearly in frequency between 8 kHz and 16 kHz once each10 msec. The average sound pressure level (SPL) during stimulation wasapproximately 100 dB at the floor of the chamber. Mice were placedwithin the chamber and allowed to acclimatize for one minute. DBA/2 micein the vehicle-treated group responded to the sound stimulus (applieduntil tonic extension occurred, or for a maximum of 60 sec) with acharacteristic seizure sequence consisting of wild running followed byclonic seizures, and later by tonic extension, and finally byrespiratory arrest and death in 80% or more of the mice. Invehicle-treated mice, the entire sequence of seizures to respiratoryarrest lasts approximately 15 to 20 seconds. The incidence of all theseizure phases in the drug-treated and vehicle-treated mice wasrecorded, and the occurrence of tonic seizures were used for calculatinganticonvulsant ED₅₀ values by probit analysis (Litchfield J. T.,Wilcoxon F. “A simplified method for evaluating dose-effectexperiments,” J. Pharmacol., 1949;96:99-113). Mice were used only oncefor testing at each dose point. Groups of DBA/2 mice (n=5-10 per dose)were tested for sound-induced seizure responses 2 hours (previouslydetermined time of peak effect) after given drug orally. All drugs inthe present study were dissolved in distilled water and given by oralgavage in a volume of 10 mL/kg of body weight. Compounds that areinsoluble will be suspended in 1% carboxymethocellulose. Doses areexpressed as weight of the active drug moiety.

The compounds of the instant invention are also expected to be useful inthe treatment of pain and phobic disorders (Am. J Pain Manag.,1995;5:7-9).

The compounds of the instant invention are also expected to be useful intreating the symptoms of manic, acute or chronic, single upside, orrecurring depression. They are also expected to be useful in treatingand/or preventing bipolar disorder (U.S. Pat. No. 5,510,381).

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the; like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsules, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 1 g according to the particularapplication and the potency of the active component. In medical use thedrug may be administered three times daily as, for example, capsules of100 or 300 mg. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use, the compounds utilized in the pharmaceutical methodof this invention are administered at the initial dosage of about 0.01mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg toabout 100 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

The following examples are illustrative of the instant invention; theyare not intended to limit the scope.

EXAMPLE 1

Reagents:

(i) TiCl₄, MeO₂CCH₂CO₂Me, pyridine, tetrahydrofuran;

(ii) N-Benzylglycine hydrochloride, Et₃N, paraformaldehyde, PhH;

(iii) Pearlman's catalyst, methanol, H₂;

(iv) 6N HCl.

2-Cyclohexylidene-malonic Acid Dimethyl Ester (2)

To 20 mL of tetrahydrofuran cooled at −78° C. was slowly added, under anargon atmosphere, TiCl₄ (1 M in CH₂Cl₂; 100 mL; 100 mmol). After theaddition was complete, the reaction mixture was warmed up to −10° C. Tothe mixture was then successively added dimethylmalonate (6.73 g; 51mmol), cyclohexanone 1 (5 g; 51 mmol) over 5 minutes and pyridine (16.4mL; 201 mmol) over 1 hour 30 minutes. The brown suspension was thenallowed to warm up to room temperature, stirred overnight and dilutedwith water (50 mL). The phases were separated, and the organic phase waswashed with water, dried over MgSO₄, and the solvent removed in vacuo.The crude oil was chromatographed over silica gel (ether/heptane 1:1) togive 2 as a pale yellow solid (6.35 g; 30 mmol; 58%).

¹H NMR (CDCl₃) δ ppm: 1.6 (m, 6H); 2.5 (m, 4H); 3.75 (s, 6H). MSES+[MW+1]⁺: 213.

2-Benzyl-2-aza-spiro[4.5]decane-4,4-dicarboxylic Acid Dimethyl EsterHydrochloride (3)

A solution of dimethyl (cyclohexylidene) malonate 2 (594 mg; 2.8 mmol),N-benzylglycine hydrochloride (1.41 g; 6.99 mmol), triethylamine (0.97mL; 6.95 mmol), and paraformaldehyde (671 mg; 22.36 mmol) in benzene (18mL) was slowly heated up to 125° C. (oil bath) (Dean-Stark). Afterstirring for 2 hours, the reaction mixture was cooled to roomtemperature, diluted with toluene (20 mL), and washed with brine. Theaqueous phase was extracted with toluene (2×10 mL). The organic phaseswere combined, dried over MgSO₄, and evaporated to give a brown oilwhich was purified on silica gel chromatography (EtOAc/heptane 1:3). Theresulting pale yellow oil was diluted in diethyl ether (10 mL), and thecompound was extracted with 2N HCl (2×5 mL). The aqueous phases werecombined, washed with diethyl ether, and concentrated in vacuo to give 3as a white solid (238 mg; 0.62 mmol; 22%).

¹H NMR (D₂O) δ ppm: 1.2 to 1.9 (m, 10H); 3.65 and 3.9 ([AB]q, 2H); 3.9(d, 6H); 4.1 and 4.25 ([AB]q, 2H); 4.65 (s, 2H); 7.6 (m, 5H). MSES+[MW+1]⁺: 3146.

2-Aza-spiro[4.5]decane-4,4-dicarboxylic Acid Dimethyl EsterHydrochloride (4)

A solution of 3 (238 mg; 0.62 mmol) and 10% Palladium hydroxide oncarbon (47 mg; 20% w/w) in methanol (10 mL) was stirred overnight at 40°C. under a hydrogen atmosphere (55 psi). The catalyst was filtered offthrough a celite pad, and the filtrate was evaporated under vacuum togive 4 as a yellow solid (170 mg; 0.58 mmol; 93%).

¹H NMR (D₂O) δ ppm: 1.2 to 1.8 (m, 10H); 3.65 (s, 2H); 3.9 (s, 6H); 4.01(s, 2H). MS ES+[MW+1]⁺: 256.

2-Aza-spiro[4.5]decane-4-carboxylic Acid Hydrochloride (5)

A solution of 4 (170 mg; 0.58 mmol) in 6N HCl (5 mL) was stirredovernight at 145° C. After cooling, the solvent was removed under vacuumto yield 5 as a pale yellow solid (153 mg; 0.58 mmol; quant.).

¹H NMR (D₂O) δ ppm: 1.39 to 1.8 (m, 10H); 3.1 (t, 1H); 3.4 ([AB]q, 2H);3.7 (d[AB]q, 2H). MS ES+[MW+1]⁺: 184. C,H,N Calc. for C₁₀H₁₇NO₂.1.75HCl.1.0OH₂O: C, 45.31; H, 7.89; N, 5.28. Observed: C, 45.65; H, 7.69; N,5.62.

EXAMPLE 1A

Reagents:

5 (i) HCl.BnNHCH₂CO₂H, Et₃N, HCHO, PhH, reflux (82%);

(ii) 6N HCl reflux (94%);

(iii) MeOH, HCl, reflux (65%);

(iv) Pd(OH)₂/C, H₂, MeOH (97%);

(v) BnOCOCl, Py, CH₂Cl₂, (88%);

(vi) Dioxane/Aq NaOH (89%);

(vii) CH₂Cl₂, (COCl)₂, HCONMe₂ then (R)-(+)-1-(2-Napthyl)ethylaminefollowed by flash chromatography (20a)—43% and (20b)—39%;

(viii) 6N HCl, THF reflux (73%);

(ix) 6N HCl, THF reflux (78%).

2-Benzyl-2-aza-spiro[4.5]decane-4-carboxylic Acid Methyl Ester (4)

A solution of (1) (4 g; 20.70 mmol), N-benzylglycine hydrochloride (10.4g; 51.57 mmol),triethylamine (7.2 mL; 51.65 mmol), and paraformaldehyde(5.2 g; 173.30 mmol) in benzene (120 mL) was refluxed for 2 hours usinga Dean-Stark apparatus. After cooling, the reaction mixture was dilutedwith toluene (200 mL) and washed with brine. The aqueous phase wasextracted with toluene (3×30 mL). The organic extracts were combined,dried over MgSO₄, and concentrated in vacuo. The crude oil was purifiedover silica-gel chromatography in EtOAc/heptane (1:3) to give a yellowoil which was diluted in ether (30 mL) and extracted with 3N HCl (3×25mL). The aqueous phase was washed with ether (2×30 mL) and wasconcentrated under vacuum to give (2) as a white powder (6.20 g; 17.08mmol) which was used without any further purification. A solution of (2)(6.2 g; 17.08 mmol) in 6N HCl (120 mL) was refluxed overnight.Evaporating the solvent in vacuo gave 5 g (16.13 mmol; 77% from (1)) of(3) as a pale yellow solid which was immediately esterified. Acetylchloride (5 mL; 70.32 mmol) was slowly added to methanol (100 mL), at 0°C., under an argon atmosphere. After stirring for 10 minutes, thissolution was transferred to a flask containing (3) (5 g; 16.13 mmol),under an argon atmosphere. The reaction mixture was then stirred at 95°C. for 3 hours. After cooling, the methanol was removed in vacuo. Theresidue was basified with saturated aqueous Na₂CO₃, and was extractedwith ether (3×30 mL). The organic phases were combined, dried overMgSO₄, and concentrated to give 3 g (10.44 mmol; 50% from (1)) of (4) asa pale yellow liquid.

¹H NMR (CDCl₃) 400 MHz δ: 1.0 to 1.7 (m, 10H); 2.25 (d, 1H); 2.65 to 2.9(m, 4H); 3.6 ([AB]q, 2H); 3.65 (s, 3H, OCH ₃)); 7.3(m, 5H, Ph). MS (ES⁺)m/e: 288 ([MH]⁺,100%).

2-Aza-spiro[4.5]decane-2,4-dicarboxylic Acid 2-Benzyl Ester 4-MethylEster (6)

A solution of (4) (3 g; 10.44 mmol) and 10% Pd (OH)₂/C (0.60 g; 20% w/w)in methanol (50 mL) was stirred for 24 hours at 40° C. under atatmosphere of dry hydrogen gas. The catalyst was filtered off through acelite pad, and the filtrate was concentrated in vacuo to.give 2 g(10.14 mmol; 97%) of (5) as a colorless oil which was used without anyfurther purification. To a solution of (5) (2 g; 10.14 mmol) in drydichloromethane (100 mL) was successively added, at 0° C., under anargon atmosphere, pyridine (2.04 mL; 25.35 mmol), andbenzylchloroformate (2.89 mL; 20.24 mmol). The reaction mixture was thenallowed to stir at room temperature for 2 days. The reaction mixture waswashed (2×50 mL) with IN HCl, dried over MgSO₄, and concentrated invacuo. The crude oil was purified by silica-gel flash chromatography inether/heptane (1:1) to give 2.97 g (8.96 mmol; 88%) of (6) as acolorless oil.

¹H NMR (CDCl₃) 400 MHz δ: 1.15 to 1.7 (m, 10H); 2.8 (m, 1H); 3.3 (m,1H); 3.45 to 3.8 (m, 6H); 5.15 ([AB]q, 2H, PhCH ₂); 7.3 (m, 5H, Ph). MS(ES⁺) m/e: 332 ([MH]⁺, 100%).

2-Aza-spiro[4.5]decane-2,4-dicarboxylic Acid 2-Benzyl Ester (7)

To a solution of (6) (300 mg; 0.9 mmol) in a mixture dioxane/water (6mL; 9:1) was added a 2 M solution of NaOH (0.90 mL; 1.8 mmol). Thereaction mixture was stirred at 35° C. for 6 hours. Solvents wereremoved in vacuo. The residue was diluted in water (15 mL) and waswashed with diethyl ether (3×10 mL). The aqueous phase was acidifiedwith 2N HCl and was extracted with ethyl acetate (3×15 mL). The ethylacetate extracts were combined, dried over MgSO₄, and concentrated togive 254 mg (0.8 mmol; 89%) of (7) as a colorless gum.

¹H NMR (CDCl₃) 400 MHz δ: 1.2 to 1.75 (m, 10H); 2.8 (m, 1H); 3.3 (m,1H); 3.5 to 3.8 (m, 3H); 5.1 (ABq, 2H); 7.3 (m, 5H). MS (ES⁺) m/e: 318([MH]⁺, 100%).

(4S,1′R)-4-(1′-Naphthalen-2-yl-ethylcarbamoyl)-2-aza-spiro[4.5]decane-2-carboxylicAcid Benzyl Ester (8a) and(4R,1′R)4-(1′-Naphthalen-2-yl-ethylcarbamoyl)-2-aza-spiro[4.5]decane-2-carboxylicAcid Benzyl Ester (8b)

To a cooled (0° C.) solution of (7) (1.71 g; 5.38 mmol) in drydichloromethane (35 mL) were successively added, under an argonatmosphere, oxalyl chloride (0.56 mL; 6.42 mmol) and dimethylformamide(20 μL; 0.26 mmol). The reaction mixture was stirred at 0° C. for 30minutes and then was allowed to stir at room temperature for 2 hours.The solvent was removed in vacuo, and the residue was diluted in drydichloromethane (35 mL). This solution was then added to a solution of(R)-(+)-1-(2-naphthyl)ethylamine (1.10 g; 6.42 mmol) and triethylamine(0.90 mL; 6.42 mmol) in dry dichloromethane (50 mL) under an argonatmosphere. The reaction mixture was stirred at room temperatureovernight. 2N HCl (30 mL) was added, and the organic and aqueous phaseswere separated. The organic phase was washed with water (30 mL), driedover MgSO₄, and concentrated to give a pale yellow oil which waspurified over silica-gel chromatography in EtOAc/heptane (1:1) to give1.1 g (2.34 mmol; 43%) of (8a) and 1.0 g (2.12 mmol; 39%) of (8b) aswhite solids.

¹H NMR (CDCl₃) 400 MHz δ: (8a): 1.2 to 1.65 (m, 13H); 2.4 (m, 1H); 3.35(d, 1H); 3.5 to 3.8 (m, 3H); 5.1 (m, 2H); 5.3 (m, 1H); 5.7 (t, 1H); 7.3to 7.8 (m, 12H). (8b): 1.2 to 1.65 (m, 13H); 2.4 (m, 1H); 3.25 (d, 1H);3.5 to 3.8 (m, 3H); 5.1 (m, 2H); 5.3 (m, 1H); 5.7 (t, 1H); 7.3 to 7.8(m, 12H). MS (ES⁺) m/e: (8a): 471 ([MH ]⁺, 100%); (8b): 471 ([MH ]⁺,100%).

(S)-2-Aza-spiro[4.5]decane4-carboxylic Acid (9a)

To a solution of (8a) (770 mg; 1.64 mmol) in THF (5 mL) was added 6Naqueous HCl (40 mL). The reaction mixture was stirred under refluxovernight. After cooling, the reaction mixture was washed with EtOAc(2×20 mL). The phases were separated, and the aqueous phase wasconcentrated to dryness under vacuum. The crude residue was dissolved in6N aqueous HCl (40 mL), and the reaction mixture was stirred underreflux for 60 hours. After cooling, the reaction mixture was washed withEtOAc (2×20 mL). The phases were separated, and the aqueous phase was!concentrated to dryness to leave a solid which was dissolved in water.Removing water under vacuum led to (9a) as a white powder (263 mg; 1.20mmol; 73%).

¹H NMR (CDCl₃) 400 MHz δ: 1.2 to 1.8 (m, 10H); 3.1 (t, 1H); 3.4 ([AB]q,2H); 3.7 (m, 2H). MS (ES⁺) m/e: 184 ([MH]⁺, 100%).

(R)-2-Aza-spiro[4.5]decane4-carboxylic Acid (9b)

(8b) (553 mg; 1.17 mmol) was converted to 200 mg (0.91 mmol; 78%) of(12b) by the same procedure for (9a) to (12a).

¹H NMR (CDCl₃) 400 MHz δ: 1.2 to 1.8 (m, 10H); 3.1 (t, 1H); 3.4 ([AB]q,2H); 3.7 (m, 2H). MS (ES⁺) m/e: 184 ([MH]⁺, 100%).

EXAMPLE 2

Reagents:

(i) BnOCH₂CHO, LiN(iPr)₂, THF, −78° C. to −20° C.;

(ii) AlCl₃, LiAlH₄, Et₂O;

(iii) BOC₂ O. dichloromethane;

(iv) MeSO₂Cl, Et₃N, dichloromethane;

(v) NaH, dimethylformamide;

(vi) Ammonium formate, 10% Pd/C, MeOH;

(vii) NalO₄, RuCl₃, CCl₄, CH₃CN, H₂O;

(viii) IN HCl (g) in ethyl acetate.

1-(2-Benzyloxy-1-hydroxy-ethyl)-cyclohexanecarbonitrile (2)

Lithium diisopropylamide was prepared by dropwise addition of n-BuLi(2.03 mL; 2.5 M in Hexanes; 5.08 mmol) to a stirred and cooled (−10° C.)solution of i-Pr₂NH (0.84 mL; 6.0 mmol) in dry tetrahydrofuran (40 mL).Stirring was continued for 20 minutes. The mixture was cooled to −78° C.and cyclohexane carbonitrile 1 (500 mg; 4.62 mmol) was added over 5minutes. After a further 30 minutes, benzyloxyacetaldehyde (0.97 mL;6.93 mmol) was added dropwise. Stirring was continued at −78° C. for 7hours. The reaction mixture was then allowed to stir overnight at −20°C. Saturated aqueous NH₄Cl was added (10 mL), and the mixture wasextracted with diethyl ether (2×20mL), dried over MgSO₄ and evaporated.The residue was purified over silica gel chromatography (ether/heptane1:1) to give 2 as a white solid (872 mg; 3.37 mmol; 73%)

¹H NMR (CDCl₃) δ: 1.1 to 1.8 (m, 9H); 2.2 (d, 1H); 2.75 (s, 1H); 3.6 to3.8 (m, 3H); 4.6 ([AB]q, 2H); 7.4 (m, 5H). MS ES+[MW+1]⁺: 259.

1-(1-Aminomethyl-cyclohexyl)-2-benzyloxy-ethanol (3)

To AlCl₃ (410 mg; 3.07 mmol) was added, at −78° C. and under an argonatmosphere, 3 mL of diethyl ether. The dry ice-bath was removed. Themixture was stirred at room temperature for 10 minutes, and then wasadded to LiAlH₄ (3.02 mL; 1 M in diethyl ether; 3.02 mmol). A solutionof 2 (300 mg; 1.16 mmol) in diethyl ether (3 mL) was then added over thecourse of 2 minutes, and the reaction mixture was stirred overnight atroom temperature. The mixture was quenched by cautious addition of water(2 mL) followed by addition of 10% H₂SO₄ (30 mL). The aqueous phase waswashed with diethyl ether (3×15 mL), basified with NaOH pellets (excess)and extracted with diethyl ether (3×15 mL). The organic phases werecombined, washed with brine, dried over MgSO₄, and evaporated to give 3as a colorless oil (230 mg; 0.87 mmol; 76%) which was used withoutfurther purification.

¹H NMR (CDCl₃) δ ppm: 1.2 to 1.7 (m, 10H); 2.75 (d, 1H); 2.95 (s, 1H);3.6 (dd, 1H); 3.7 (dd, 1H); 4.6 ([AB]q, 2H); 7.3 (m, 5H). MS ES+[MW+1]⁺:264.

[1-(2-Benzyloxy-1-hdroxy-ethyl)-cyclohexylmethyl]-carbamic AcidTert-butyl Ester (4)

A solution of 3 (244 mg; 0.92 mmol) and BOC₂O (242 mg; 1.11 mmol) inCH₂Cl₂ (8 mL) was stirred at room temperature for 24 hours under anargon atmosphere. The solvent was removed under vacuum, and the crudeoil was purified over silica gel chromatography (ether/heptane 1:1) togive 4 as a colorless oil (298 mg; 0.82 mmol; 89%).

¹H NMR (CDCl₃) δ ppm: 1.1 to 1.6 (m, 10H); 1.4 (s, 9H); 2.8 (s, 1H); 3.1(dd, 1H); 3.35 (dd, 1H); 3.5 (t, 1H); 3.65 (dd, 1H); 3.75 (dd, 1H); 4.6([AB]q, 2H); 5.5 (bs, 1H); 7.3 (m, 5H). MS ES+[MW+1]⁺: 364.

Methanesulfonic Acid2-Benzyloxy-1-[1-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-ethylester (5)

To a cooled (−10′ C.) solution of 4 (290 mg; 0.79 mmol) andtriethylamine (0.33 mL; 2.39 mmol), in CH₂Cl₂ (5 mL) was added, under anargon atmosphere, MsCl (0.154 mL; 1.93: mmol) diluted in CH₂Cl₂ (0.5mL). The reaction mixture was then allowed to stir at room temperaturefor 2 days. The solvent was removed under vacuum, and the residue wasdiluted in diethyl ether, washed with water, dried over MgSO₄, andconcentrated. The crude oil was purified over silica gel chromatography(ether/heptane 1:1) to give 5 as a colorless oil (200 mg; 0.45 mmol;57%).

¹H NMR (CDCl₃) δ ppm: 1.2 to 1.6 (m, 10H); 1.2 (s, 9H); 3 (s, 1H); 3.05(dd, 1H); 3.25 (dd, 1H); 3.8 (m, 2H); 4.55 ([AB]q, 2H); 4.75 (m, 1H);5.05 (m, 1H); 7.3 (m, 5H). MS ES+[MW+1]⁺: 442

1-Benzyloxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic Acid tert-butylEster (6)

A solution of 5 (2.53 g; 5.73 mmol) and NaH (460 mg; 60% w/w in oil;11.47 mmol) in dry DI4F (115 mL) was stirred at 45° C. for 1 hour underan argon atmosphere. The reaction was quenched by cautious addition ofsaturated NH₄Cl (200 mL), and the aqueous phase was extracted withdiethyl ether (2×100 mL). The organic phases were combined, dried overMgSO₄, and evaporated. The residue was purified over silica gelchromatography (ether/heptane 1:2) to give 6 as a colorless oil (1.20,g;3.48 mmol; 59%).

¹H NMR (CDCl₃) δ ppm: 1.2 to 1.8 (m, 10H); 1.4 (s, 9H); 3.45 ([AB]q,2H); 3.7 (m, 2H); 3.85 (m, 1H); 4.55 ([AB]q, 2H); 7.3 (m, 5H). MSES+[MW+1]⁺: 346.

1-Hydroxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic Acid Tert-butylEster (7)

A solution of 6 (349 mg; 1.01 mmol), ammonium formate (638 mg; 10.1mmol) and 10% Pd/C (349 mg; 1 eq. w/w) in methanol (20 mL) was heated toreflux for 2 hours. Ammonium formate (638 mg; 10.1 mmol) and 10% Pd/C(175 mg; 0.5 eq. w/w) were added, and the reaction mixture was refluxedfor a further 2 hours. After cooling, the catalyst was filtered offthrough a celite pad, and the filtrate was evaporated. The crude oil waspurified over silica gel chromatography (ether /heptane 4:1) to give 7as a white solid (193 mg; 0.76 mmol; 75%).

¹H NMR (CDCl₃) δ ppm: 1.1 to 1.8 (m, 10H); 1.45 (s, 9H); 3.55 ([AB]q,2H); 3.7 (m, 1H); 3.9 (m, 2H); 4.45 (bs, 1H). MS ES+[MW+1]⁺: 256. C,H,NCalc.: C, 65.85; H. 9.87; N, 5.48. Observed: C, 65.54; H, 9.65; N, 5.39.

2-Aza-spiro[3.5]nonane-1,2-dicarboxylic Acid 2-Tert-butyl Ester (8)

To 7 (212 mg; 0.83 mmol) dissolved in a mixture of CCl₄ (1.7 mL), CH₃CN(1.7 mL), and water (2.5 mL) was added NaIO₄ (710 mg; 3.32 mmol). After15 minutes, hydrated RuCl₃ (4.8 mg; 2.2% mol) was added, and thereaction mixture was stirred at room temperature for 2 hours. Themixture was then extracted with CH₂Cl₂ (3×5 mL), washed with water,dried over MgSO₄ and concentrated. The crude oil was diluted in diethylether (5 mL) and saturated aqueous Na₂CO₃ (5 mL) was added. The aqueousphase was washed with diethyl ether (3×5 mL), acidified up to pH=3 withIN HCl and extracted with diethyl ether (3×5 mL). The organic phaseswere combined, washed with water and concentrated in vacuo to give 8 asa white solid (185 mg; 0.69 mmol; 83%).

¹H NMR (CDCl₃) δ ppm: 1.2 to 1. 8 (m, 10H); 1.5 (s, 9H); 3.6 ([AB]q,2H); 4.3 (s, 1H). MS ES+[MW+1]⁺: 270. C,H,N Calc.: C, 62.43; H, 8.60; N,5.20. Observed: C, 62.40; H, 8.75; N, 5.01.

2-Aza-spiro[3.5]nonane-1-carboxylic Acid Hydrochloride (9)

Compound 8 (21.5 mg; 0.079 mmol) was dissolved in a dry 1 M HCl(g)solution in ethyl acetate (0.4 mL; 0.4 mmol) under an argon atmosphere.The reaction mixture was stirred at room temperature for 5 hours. Thewhite precipitate was collected by filtration and washed several timeswith dry diethyl ether (2 mL) and dried under vacuum to give 9 as awhite powder (15.2 mg; 0.074 mmol; 92%).

¹H NMR (CDCl₃) δ ppm: 1.03 to 1.84 (m, 10H); 3.7 ([AB]q, 2H); 4.4 (s,1H). MS ES+[MW+1]⁺: 170. MP: 163-165° C. C,H,N Calc. C₉H₁₅NO₂.1.0HCl: C,52.55; H, 7.84; N, 6.81. Observed: C, 52.50; H, 7.74; N, 6.88.

EXAMPLE 3

Reagents:

(i) MeNO₂, (Bu)₄N⁺F⁻; tetrahydrofuran;

(ii) Ni sponge, H₂, MeOH;

(iii) (BOC)₂O, 4-dimethylamino pyridine, Et₃N, tetrahydrofuran;

(iv) LiN(iPr)₂, Me₃CO₂CCH₂Br, tetrahydrofuran;

(v) LiBHEt₃, tetrahydrofuran then Et₃SiH, BF₃.Et₂O, dichloromethane;

(iv) CF₃CO₂H, dichloromethane.

2-Nitromethyl-cyclohexanecarboxylic Acid Methyl Ester (2)

A solution of cyclohex-1-enecarboxylic acid methyl ester 1 (5.15 g; 36.7mmol), tetrabutyl ammonium fluoride (55.10 mL; 1 M in THF; 55.1 mmol)and nitromethane (3.97 mL; 73.5 mmol) in tetrahydrofuran (60 mL) washeated to reflux for 4 hours. After cooling to room temperature, thereaction mixture was diluted with diethyl ether (500 mL), washed with 2NHCl (2×100 mL) and then with brine (2×100 mL). The phases wereseparated. The organic phase was dried over MgSO₄ and concentrated invacuo. The crude mixture was purified over silica gel chromatography(EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as apale yellow liquid.

¹H NMR 2 (CDCl₃) δ ppm: 1.1 to 2.4 (m, 10H); 3.7 (s, 3H); 4.25 (dd, 1H);4.45 (dd, 1H). MS ES+[MW+1]⁺: 202.

Octahydro-isoindol-1-one (3)

A solution of 2 (5.42 g; 27 mmol) and nickel sponge catalyst (cat.) inmethanol (100 mL) was stirred at 30° C. for 4 hours under a hydrogenatmosphere (70 psi). The catalyst was filtered off through a celite pad,and the filtrate was concentrated under vacuum. Recrystallization of thecrude solid (ether/heptane) gave 3 (3.69 g; 26.5 mmol; 98%) as a whitepowder.

¹H NMR (CDCl₃) δ ppm: 1.2 to 2.4 (m, 10H); 2.9 (d, 1H); 3.35 (m, 1H);5.7 (bs, 1H). MS ES+[MW+1]⁺: 140.

1-Oxo-octahydro-isoindole-2-carboxylic acid Tert-butyl ester (4)

To 3 (835 mg, 6 mmol) in suspension in tetrahydrofuran (7 mL) wassuccessively added, under an argon atmosphere, 4-dimethylaminopyridine(18.3 mg; 0.15 mmol), triethylamine (0.84 mL; 6 mmol) and BOC₂O (2.62 g;12 mmol). The reaction mixture was stirred at room temperature for 3days. The solvent was removed under vacuum. The residue was diluted withdiethyl ether (20 mL) and washed with water (2×10 mL). The phases wereseparated, and the organic phase was dried over MgSO₄ and concentrated.The crude oil was purified over silica gel chromatography (ether/heptane1:1) to give 4 (986 mg; 4.1 mmol; 70%) as a white solid.

¹H NMR (CDCl₃) δ ppm: 1.2 to 2.6 (m, 10H); 1.5 (s, 9H); 3.4 (d, 1H); 3.6(dd, 1H). MS ES+[MW+1]⁺: 240.

[3aS-(3α7aα)]-7a-tert-Butoxycarbonylmethyl-1-oxo-octahydro-isoindole-2-carboxylicacid Tert-butyl Ester (5)

Lithium diisopropylamide was prepared by dropwise addition of n-BuLi(1.39 mL; 2.5 M in hexanes; 3.47 mmol) to a stirred and cooled (−10° C.)solution of i-Pr₂NH (0.63 mL; 4.5 mmol) in dry tetrahydrofuran (33 mL).Stirring was continued for 20 minutes. The mixture was cooled to −78° C.and 4 (832 mg; 3.47 mmol), dissolved in dry tetrahydrofuran (2 mL), wasadded over 5 minutes. After a further 30 minutes, tert-Butylbromoacetate(0.77 mL; 5.21 mmol) was added dropwise. The mixture was then allowed towarm up to room temperature. N,N-Dimethylpropyleheurea (5 mL; 41.3 mmol)was added, and the reaction mixture was heated up to 75° C. for 5 hours.After cooling, saturated NH₄Cl (10 mL) was added, and the mixture wasextracted with diethyl ether (2×20 mL). The phases were separated, andthe organic phase was dried over MgSO₄ and concentrated. The residue waspurified over silica gel chromatography (ether/heptane 1:1) to give 5(840 mg; 2.37 mmol; 70%) as a colorless oil.

¹H NMR (CDCl₃) δ ppm: 1.2 to 1.7 (m, 8H); 1.4 (s, 9H); 1.55 (s, 9H); 2.5(m, 1H); 2.55 [AB]q, 2H); 3.45 (dd, 1H); 3.75 (dd, 1H). MS ES+[MW+23]⁺:376.

[3aS-(α7aα)]-3a-tert-Butoxycarbonylmethyl-octahydro-isoindole-2-carboxylicAcid Tert-butyl Ester (6)

To a cooled (−78° C.) solution of 5 (340 mg; 0.96 mmol) in drytetrahydrofuran (6 mL) was added, under an argon atmosphere, LiBHEt₃(1.15 mL; 1 M in THF; 1.15 mmol). The reaction mixture was quenchedafter 4 hours by addition of saturated aqueous NaHCO₃ (1.8 mL). Themixture was allowed to warm up to 0° C. Thirty percent H₂O₂ (5 drops)was added, and the mixture was stirred at 0° C. for a further 30minutes. The solvent was then removed under vacuum, and the aqueousphase was extracted with CH₂Cl₂ (3×5 mL). The organic phases werecombined, dried over MgSO₄, and concentrated. To the crude residue inCH₂Cl₂ (15 mL) was added, at −78° C., under an argon atmosphere, Et₃SiH(0.15 mL; 0.96 mmol) and BF₃.Et₂O (0.135 mL; 1.05 mmol). After stirringfor 30 minutes, a further Et₃SiH (0.15 mL; 0.96 mmol) and BF₃.Et₂O(0.135 mL; 1.05 mmol) were added, and the reaction mixture was stirredat −78° C. for 3 hours. Quenching was achieved at −78° C. by addition ofsaturated aqueous NaHCO₃ (1.5 mL). The phases were separated, and theorganic phase was dried over MgSO₄ and concentrated. The residue waspurified over silica gel chromatography (Et₂O/heptane 1:1) to give 6(157 mg; 0.46 mmol; 48%) as a colorless oil.

¹H NMR (CDCl₃) δ ppm: 1.2 to 1.4 (m, 26H); 2 (m, 1H); 2.15 (d, 1H); 2.55(dd, 1H); 3.2 to 3.5 (m, 4H). MS ES+[MW+1]⁺: 340.

[3aS-(3α7aα)]-(Octaahydro-isoindol-3a-yl)-acetic acid trifluoroacetate(7)

A solution of 6 (100 mg; 0.29 mmol) in a mixture CH₂Cl₂/TFA (2 mL;50:50) was stirred at room temperature for 2 hours. The solvent wasremoved under vacuum. The residue was diluted with water (2 mL) andwashed with ether (2×2 mL). The phases were separated, and the aqueousphase was concentrated under vacuum to give 7 (60 mg; 0.17 mmol; 69%) asa pale yellow gum.

¹H NMR (D₂O) δ ppm: 1.4 to 1.8 (m, 8H); 2.3 (m, 1H); 2.5 (d, 1H); 2.95(d, 1H); 3.35 to 3.95 (m, 4H). MS ES+[MW+1]⁺: 184. C,H,N Calc. forC₁₀H₁₇NO₂.1.0C₂HF₃O₂.0.7H₂O: C, 46.51; H, 6.31; N, 4.52. Observed: C,46.48; H, 5.98; N, 4.57.

The following compounds can also be prepared by the above syntheticmethods:

7-Methyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;

7,8-Dimethyl,2-aza-spiro[4.4]nonane-4-carboxylic acid;

7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

7,9-Dimethyl-2-aza-spiro[4.5]decane-4-carboxylic acid;

Spiro [bicyclo[3.3.1]nonane-9,3′-pyrrolidine]-4′-carboxylic acid;

Spiro[pyrrolidine-3,2′-tricyclo[3.3.1.1^(3,7)]decane]-4-carboxylic acid;

3-Amino-6-methyl-spiro[3.5]nonane-1-carboxylic acid;

3-Amino-6,8-dimethyl-spiro[3.5]nonane-1-carboxylic acid;

4-Amino-7-methyl-spiro[4.5]decane-1-carboxylic acid;

4-Amino-7,9-dimethyl-spiro[4.5]decane-1-carboxylic acid;

3-Amino-6-methyl-spiro[3.4]octane-1-carboxylic acid;

3-Amino-6,7-dimethyl-spiro[3.4]octane-1-carboxylic acid;

4-Amino-7-methyl-spiro[4.4]nonane-1-carboxylic acid; and

4-Amino-7,8-dimethyl-spiro[4.4]nonane-1-carboxylic acid.

In all of the above compounds, all stereocenters may be R or S.

For example:

What is claimed is:
 1. A compound of formula

or a pharmaceutically acceptable salt thereof wherein m is 1; s is aninteger of from 1 to 3; and t is an integer of from 0 to
 2. 2. Acompound selected from:Spiro[bicyclo[3.3.1]nonane-9,3′-pyrrolidine]-4′-carboxylic acid; andSpiro[pyrrolidine-3,2′-tricyclo[3.3.1.1^(3,7)]decane]-4-carboxylic acid.3. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 4. A method for treating anxiety comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 to a mammal in need of said treatment.